Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2005-04-27 to 2005-08-08
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study reports): JNJ-117676-AAA (T000263)
- Physical state: solid (powder)
- Appearance: White, slight beige amorphous, crystalline, micropowder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: the test item was delivered by the Sponsor with Batch number: CODE: 8693
- Expiration date of the lot/batch: 31 December 2005
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature (range of 20 ± 5 °C), light protected
- Stability under test conditions: no data, but stable under storage conditions
- Solubility and stability of the test substance in the solvent/vehicle: no data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
Purified water was found to be a suitable vehicle

Test animals

Species:
rat
Strain:
other: HanRcc: Wist (SPF)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: 11 - 13 weeks
- Weight at study initiation: 185.3 g (mean)
- Fasting period before study: 19 hours (access to water was permitted)
- Housing: in groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 4/05, ad libitum
- Water (e.g. ad libitum): community tap water from Füllinsdorf, ad libitum
- Acclimation period: 2005-04-27 to 2005-05-03 (females, 2000 mg/kg); 2005-04-29 to 2005-05-05 (females, 300 mg/kg); 2005-05-10 to 2005-05-16 (females, 300 mg/kg)


ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 22 +/- 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: : purified water prepared at RCC Ltd.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.2 g/mL or 0.03 g/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The vehicle was chosen after a solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): not applicable
- Purity: reported as purified


MAXIMUM DOSE VOLUME APPLIED:
- 10 mL/kg bw


DOSAGE PREPARATION (if unusual):
- not applicable


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: no data
Doses:
2000 mg/kg bw for one group of 3 females, or 300 mg/kg bw for two groups of 3 females each
No. of animals per sex per dose:
three groups each with three females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded; all animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15; mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15; Body weights were recorded on day 1 (prior to administration) and on days 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Mortality:
One 2000 mg/kg treated animal had to be killed in extremis for ethical reasons approximately 2 1/2 hours after test item application. The two other animals also treated at 2000 mg/kg were found dead approximately 1 1/2 hours after treatment. All 300 mg/kg treated animals survived until the end of the study period.
Clinical signs:
In the high dose group, slightly ruffled fur was observed in all animals from the 0.5- to the 1 -hour reading. Moderate tremor and ventral recumbency were seen in two animals at the 1-hour examination and severe tremor and ventral recumbency were noted in the third animal at the 2-hour reading.

In the 300 mg/kg dose groups, slightly ruffled fur was observed in three out of 6 animals from the 1- or 2-hour to the 5-hour examination. One animal additionally showed hunched posture from the 2- to the 3-hour examination. No clinical signs were observed in the remaining three animals during the course of the study.
Body weight:
The body weights of the animals were within the range commonly recorded for this strain and age.
Gross pathology:
Liquid contents were noted in the stomach of all three animals treated at 2000 mg/kg at their unscheduled necropsy. One 300 mg/kg-treated animal showed congestion of the lungs, whereas no macroscopic findings were recorded in the remaining animals treated at 300 mg/kg at their scheduled necropsies.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The purpose of the study was to assess the acute toxicity of the test substance when administered by a single oral gavage to rats, followed by an observation period of 14 days. The LD50 of the test substance after single oral administration to female rats, observed over a period of 14 days was greater than 300 mg/kg bw and less than 2000 mg/kg bw.